Phosphoethanolamine Accumulation Protects Cancer Cells under Glutamine Starvation through Downregulation of PCYT2
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ABSTRACT:
PROVIDER: PRJNA561847 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10027927_1.fastq.gz | Fastqsanger.gz | |||
| SRR10027927_2.fastq.gz | Fastqsanger.gz | |||
| SRR10027928_1.fastq.gz | Fastqsanger.gz | |||
| SRR10027928_2.fastq.gz | Fastqsanger.gz | |||
| SRR10027929_1.fastq.gz | Fastqsanger.gz |
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Project description:The conditions of the tumor microenvironment, such as nutrient starvation, play critical roles in cancer progression. However, the role of glutamine deprivation in cancer progression is not studied as extensively as that of hypoxia. Here, we show that glutamine starvation triggered down-regulation of PCYT2 by stimulating accumulation of PEtn. Interestingly, glutamine upregulated series of glutamine-responsive genes, not only PCYT2. Furthermore, glutamine-responsive genes were associated with overall survival of cancer patients. Thus, our findings show that glutamine responsive genes such as PCYT2 are key for progression of cancer cells, partly protecting cancer cells to glutamine starvation.
2019-08-24 | GSE136289 | GEO
Project description:Numerous mechanisms to support cells under conditions of transient nutrient starvation have been described. The tumor suppressor protein p53 can contribute to the adaptation of cells to metabolic stress through various mechanisms that may help cancer cell survival in nutrient limiting conditions. We show here that p53 helps cancer cells to survive glutamine starvation by promoting the expression of SLC1A3, an aspartate/glutamate transporter that allows the utilization of aspartate to support cells in the absence of extracellular glutamine. Under glutamine deprivation, SLC1A3 expression maintains electron transport chain and tricarboxylic acid cycle activity, promoting de novo glutamate, glutamine and nucleotide synthesis to rescue cell viability. Tumor cells with high levels of SLC1A3 expression are resistant to glutamine starvation and SLC1A3 depletion retards the growth of these cells in vitro and in vivo, suggesting a therapeutic potential for SLC1A3 inhibition.
2018-06-28 | GSE116087 | GEO
Project description:Glutamine addiction represents a metabolic vulnerability of cancer cells although effective therapeutic targeting of the pathways involved remains to be realized. Here, we disclose the critical role of IFRD1 (interferon-related developmental regulator 1) in the adaptive survival of hepatocellular carcinoma cells (HCC) during glutamine starvation. The induction and translocation of IFRD1 to the endoplasmic reticulum inhibits autophagy by promoting proteasomal degradation of the key autophagy regulator ATG14 in a TRIM21-dependent manner. On the contrary, enforced IFRD1 loss increases autophagy flux leading to cell death. This effect is largely realized through the autophagy-dependent degradation of histone H1.0 causing globally enhanced chromatin accessibility associated with unchecked increases in ribosome and protein biosynthesis . This in turn leads to metabolic exhaustion and death under glutamine starvation. Practically, IFRD1 depletion in preclinical HCC models potentiates glutamine limiting strategies including synergizing with the glutaminase-1 selective inhibitor CB-839. Thus, IFRD1 supports the adaptive survival of cancer cells under glutamine starvation, with potential as a therapeutic target in anti-cancer applications.
2024-03-23 | GSE217406 | GEO
Project description:Corynebacterium glutamicum, a gram-positive soil bacterium used for the industrial production of amino acids such as L-glutamate and L-lysine, is able to use a number of different nitrogen sources, such as ammonium, urea, or creatinine. In this communication, we show that L-glutamine serves as an excellent nitrogen source for C. glutamicum and allows similar growth rates in glucose minimal medium as ammonium. A transcriptome comparison revealed a strong induction of the nitrogen starvation response when glutamine was used as nitrogen source. Subsequent growth experiments with a variety of mutants defective in nitrogen metabolism showed that glutamate synthase is crucial for glutamine utilization, while a putative glutaminase is dispensable under the experimental conditions used. The fact that the glutamate synthase encoding gltBD operon is under strict nitrogen control explains the necessity for induction of the nitrogen starvation response. The paradox situation that the nitrogen starvation response is induced although intracellular L-glutamine levels are high has implications on nitrogen sensing. In contrast to other gram-positive and gram-negative bacteria such as Bacillus subtilis, Salmonella typhimurium, and Klebsiella pneumoniae, a drop in glutamine concentration obviously does not serve as a nitrogen starvation signal in C. glutamicum.
2010-10-05 | GSE19779 | GEO
Project description:Corynebacterium glutamicum, a gram-positive soil bacterium used for the industrial production of amino acids such as L-glutamate and L-lysine, is able to use a number of different nitrogen sources, such as ammonium, urea, or creatinine. In this communication, we show that L-glutamine serves as an excellent nitrogen source for C. glutamicum and allows similar growth rates in glucose minimal medium as ammonium. A transcriptome comparison revealed a strong induction of the nitrogen starvation response when glutamine was used as nitrogen source. Subsequent growth experiments with a variety of mutants defective in nitrogen metabolism showed that glutamate synthase is crucial for glutamine utilization, while a putative glutaminase is dispensable under the experimental conditions used. The fact that the glutamate synthase encoding gltBD operon is under strict nitrogen control explains the necessity for induction of the nitrogen starvation response. The paradox situation that the nitrogen starvation response is induced although intracellular L-glutamine levels are high has implications on nitrogen sensing. In contrast to other gram-positive and gram-negative bacteria such as Bacillus subtilis, Salmonella typhimurium, and Klebsiella pneumoniae, a drop in glutamine concentration obviously does not serve as a nitrogen starvation signal in C. glutamicum. Three biological replicates were performed. To analyse how L-glutamine influences global gene expression when used as sole nitrogen source instead of ammonium, DNA microarray analyses were performed. For this purpose RNA was isolated from exponentially growing cells cultivated in CgXII medium containing glucose as carbon source and either L-glutamine or ammonium sulphate as nitrogen source.
2010-10-05 | E-GEOD-19779 | biostudies-arrayexpress
Project description:Cancer cells heavily depend on the amino acid, glutamine, to meet the demands associated with growth and proliferation. Due to its rapid consumption, cancer cells frequently undergo glutamine starvation in vivo. We and others have shown that p53 is a critical regulator in metabolic stress resistance. To better understand the molecular mechanisms by which p53 activation promotes cancer cell adaptation to glutamine deprivation, we identified p53-dependent genes that are induced upon glutamine deprivation using RNA-seq analysis. We show that Slc7a3, an arginine transporter, is significantly induced by p53. We show the concomitant rise in intracellular arginine levels following glutamine deprivation is dependent on p53. The influx of arginine has minimal effect on known metabolic pathways upon glutamine deprivation. Instead, we found arginine serves as an effector for mTORC1 activation to promote in vitro and in vivo cell growth in response to glutamine starvation. Therefore, we identify a novel p53-inducible gene that contributes to the metabolic stress response.
2019-05-15 | GSE125782 | GEO
Project description:Algal biofuel production requires an input of synthetic nitrogen fertilizer. Fertilizer synthesized via the Haber-Bosch process produces CO2 as a waste by-product and represents a substantial financial and energy investment. Reliance on synthetic fertilizer attenuates the environmental significance and economic viability of algae production systems. To lower fertilizer input, the waste streams of algal production systems can be recycled to provide alternative sources of nitrogen such as amino acids to the algae. The halophytic green alga Dunaliella viridis can use ammonium (NH4+) derived from the abiotic degradation of amino acids, and previously, supplementation of NH4+ from glutamine (GLN) degradation was shown to support acceptable levels of growth and increased neutral lipid production compared to nitrate. To understand the effect of glutamine-released NH4+ on algae growth and physiology, metabolite levels, growth parameters, and transcript profiles of D. viridis cultures were observed in a time course after transition from media containing nitrate as a sole N source to medium containing GLN, glutamate (GLU), or a N-depleted medium. Growth parameters were similar between GLN (NH4+) and nitrate supplemented cultures, however, metabolite data showed that the GLN supplemented cultures (NH4+) more closely resembled cultures under nitrogen starvation (N-depleted and GLU supplementation). Neutral lipid accumulation was the same in nitrate and glutamine-derived NH4+ cultures. However, glutamine-derived NH4+ caused a transcriptional response in the immediate hours after inoculation of the culture. The strong initial response of cultures to NH4+ changed over the course of days to closely resemble that of nitrogen starvation. These observations suggest that release of NH4+ from glutamine was sufficient to maintain growth, but not high enough to trigger a cell transition to a nitrogen replete state. Comparative transcript profiling of the nitrogen-starved and nitrate-supplied cultures show an overall downregulation of fatty acid synthesis and a shift to starch synthesis and accumulation. The results indicate that a continuous, amino acid derived slow release of NH4+ to algae cultures could reduce the amount of synthetic nitrogen needed for growth, but optimization is needed to balance nitrogen starvation and cell division.
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Project description:ATAC-seq analysis in KPC1199 murine PDAC cell line with or without glutamine starvation
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Project description:Cultured cancer cells frequently rely on the consumption of glutamine and its subsequent hydrolysis to glutamate by the mitochondrial enzyme glutaminase (GLS). However, this metabolic addiction can be lost in the tumor microenvironment (TME), rendering GLS inhibitors ineffective in the clinic. Here, we show that seemingly glutamine-addicted breast cancer cells ultimately adapt to chronic glutamine starvation, or targeted GLS inhibition, via the AMPK-mediated upregulation of the serine synthesis pathway (SSP). In this context, the key product of the SSP is not serine itself, but a-ketoglutarate (a-KG). Mechanistically, we find that the phylogenetically distinct transaminase phosphoserine aminotransferase 1 (PSAT1) has a unique capacity for sustained a-KG production when glutamate is severely depleted. Breast cancer cells with intrinsic or acquired resistance to glutamine starvation or GLS inhibition are highly dependent on SSP-supplied a-KG. Accordingly, pharmacological disruption of the SSP prevents adaptation to glutamine blockade, yielding a potent drug synergism that abolishes breast tumor growth in vivo. These findings highlight how metabolic redundancy can be context dependent, with the catalytic properties of different metabolic enzymes that act on the same substrate determining which pathways can support tumor growth in a particular nutrient environment. This in turn has practical consequences for therapies targeting cancer metabolism.
2024-07-05 | GSE263696 | GEO
Project description:IFRD1 promotes tumor cells “low-cost” survival under glutamine starvation via inhibiting histone H1.0 nucleophagy
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